Antipsychotics have been in clinical use for more than half a century. Actions at various receptor sites, notably dopamine D2, serotonin 5-HT2A, and/or 5-HT1A receptors, are critically important for the therapeutic effect of antipsychotic drugs. How these actions at the neurobiological level translate into improvement of psychotic symptoms remains unresolved. The Principal Investigator's long-term goal is to understand the behavioral and neurobiological mechanisms of action of antipsychotic drugs. The objective of this application is to identify the behavioral mechanisms of antipsychotic action through a preclinical approach. The project hypothesis is that antipsychotic drugs achieve their anti-psychotic effect via a dual action: (a) selectively weakening the aberrant motivational salience of stimuli (e.g., psychotic thoughts or abnormal perceptions, internal and external cues) and (b) producing a drug interoceptive state that allows the weakening effect on motivational salience of stimuli to be maintained over time. A conditioned avoidance response (CAR) model and phencyclidine (PCP)-induced hyperlocomotion model based on repeated treatment regimens will be innovatively used to test this hypothesis. Aim 1 is designed to examine the weakening of motivational salience action in the CAR model. Aim 2 is to characterize the second proposed mechanism of antipsychotic action: the interoceptive drug state using the CAR model. Aim 3 is structured to use the phencyclidine (PCP)-induced hyperlocomotion model to cross-validate findings from the first two aims and further test our hypothesis. This project is innovative because several novel experimental manipulation techniques will be employed to characterize the exact psychological processes affected by antipsychotics and tease apart the ones relevant to antipsychotic action from irrelevant ones. In addition, multiple behavioral models sensitive to antipsychotic action will be used to cross-validate findings and test alternative hypotheses. Because antipsychotics will be directly compared with non-antipsychotics (e.g. chlordiazepoxide, fluoxetine, and citalopram), the reliability of data and the specificity of drug action will be greatly enhanced. Finally, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical condition and ensure the mechanisms identified are applicable to clinics. PUBLIC HEALTH RELEVANCE: How antipsychotic drugs work in the brain and change the psychological processing to achieve their therapeutic effects is unknown. This project is designed to reveal the psychological mechanisms of how antipsychotic drugs work. Successful project completion is expected to enhance our understanding of the behavioral and neurobiological mechanisms of antipsychotic action. Such knowledge will, in turn, enhance our understanding of the neurobiological basis of psychosis and help screen future novel antipsychotic drugs.